Deletion or inhibition of soluble epoxide hydrolase protects against brain damage and reduces microglia-mediated neuroinflammation in traumatic brain injury
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Tai-Ho Hung1, Song-Kun Shyue2, Chun-Hu Wu3, Chien-Cheng Chen4, Chao-Chang Lin4, Che-Feng Chang5 and Szu-Fu Chen4,6
1Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Taipei and College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
2Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
3Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
4Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China
5Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA
6Departments of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, Republic of China
Szu-Fu Chen, email: [email protected]
Keywords: soluble epoxide hydrolase, traumatic brain injury, microglia, inflammation, AUDA
Received: February 15, 2017 Accepted: August 17, 2017 Published: September 21, 2017
Traumatic brain injury (TBI) induces a series of inflammatory processes that contribute to neuronal damage. The present study investigated the involvement of soluble epoxide hydrolase (sEH) in neuroinflammation and brain damage in mouse TBI and in microglial cultures. The effects of genetic deletion of sEH and treatment with an sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), on brain damage and inflammatory responses were evaluated in mice subjected to controlled cortical impact. The anti-inflammatory mechanism of sEH inhibition/deletion was investigated in vitro. TBI-induced an increase in sEH protein level in the injured cortex from 1 h to 4 days and sEH was expressed in microglia. Genetic deletion of sEH significantly attenuated functional deficits and brain damage up to 28 days post-TBI. Deletion of sEH also reduced neuronal death, apoptosis, brain edema, and BBB permeability at 1 and 4 day(s). These changes were associated with markedly reduced microglial/macrophage activation, neutrophil infiltration, matrix metalloproteinase-9 activity, inflammatory mediator expression at 1 and 4 day(s), and epoxyeicosatrienoic acid (EET) degradation at 1 and 4 day(s). Administration of AUDA attenuated brain edema, apoptosis, inflammatory mediator upregulation and EET degradation at 4 days. In primary microglial cultures, AUDA attenuated both LPS- or IFN-γ-stimulated nitric oxide (NO) production and reduced LPS- or IFN-γ-induced p38 MAPK and NF-κB signaling. Deletion of sEH also reduced IFN-γ-induced NO production. Moreover, AUDA attenuated N2A neuronal death induced by BV2 microglial-conditioned media. Our results suggest that inhibition of sEH may be a potential therapy for TBI by modulating the cytotoxic functions of microglia.
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